Studies in cultured skin fibroblasts have revealed the presence of a defect in the regulation of sterol and fatty-acid synthesis by medium lipids in familial hypercholesterolemia (FH). The primary defect is thought to be in the cell surface receptors for low-density lipoproteins. Clinical, laboratory and genetic studies suggest the presence of several genotypes in FH. We plan to study in detail the regulation of sterol and fatty-acid synthesis in cultured fibroblasts in different variants of FH and assess the value of various fibroblasts assays in the diagnosis and classification of hereditary lipoproteinemias. Methods to be used include measurements of the rate of incorporation of acetate into the various lipid fractions, the activities of several enzymes involved in these pathways and the binding of low-density lipoproteins (LDL) to cell surface. The binding studies will be done by using LDL labelled with I125 Iodine as well as LDL conjugated to ferritin.